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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adenosine receptor agonists produce a wide variety of therapeutically useful pharmacologies. However, to date they have failed to undergo successful clinical development due to dose-limiting side effects. Adenosine kinase inhibitors (AKIs) represent an alternative strategy, since AKIs may raise local adenosine levels in a more site- and event-specific manner and thereby elicit the desired pharmacology with a greater therapeutic window. Starting with 5-iodotubercidin (IC50 = 0.026 microM) and 5'-amino-5'-deoxyadenosine (IC50 = 0.17 microM) as lead inhibitors of the isolated human AK, a variety of pyrrolo[2,3-d]pyrimidine nucleoside analogues were designed and prepared by coupling 5-substituted-4-chloropyrrolo[2,3-d]pyrimidine bases with ribose analogues using the sodium salt-mediated glycosylation procedure. 5'-Amino-5'-deoxy analogues of 5-bromo- and 5-iodotubercidins were found to be the most potent AKIs reported to date (IC50S < 0.001 microM). Several potent AKIs were shown to exhibit anticonvulsant activity in the rat maximal electric shock (MES) induced seizure assay.
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PMID:Adenosine kinase inhibitors. 1. Synthesis, enzyme inhibition, and antiseizure activity of 5-iodotubercidin analogues. 1095 96

Adenosine, through activation of membrane-bound receptors, has been reported to have neuroprotective properties during strokes or seizures. The role of astrocytes in regulating brain interstitial adenosine levels has not been clearly defined. We have determined the nucleoside transporters present in rat C6 glioma cells. RT-PCR analysis, (3)H-nucleoside uptake experiments, and [(3)H]nitrobenzylthioinosine ([(3)H]NBMPR) binding assays indicated that the primary functional nucleoside transporter in C6 cells was rENT2, an equilibrative nucleoside transporter (ENT) that is relatively insensitive to inhibition by NBMPR. [(3)H]Formycin B, a poorly metabolized nucleoside analogue, was used to investigate nucleoside release processes, and rENT2 transporters mediated [(3)H]formycin B release from these cells. Adenosine release was investigated by first loading cells with [(3)H]adenine to label adenine nucleotide pools. Tritium release was initiated by inhibiting glycolytic and oxidative ATP generation and thus depleting ATP levels. Our results indicate that during ATP-depleting conditions, AMP catabolism progressed via the reactions AMP --> IMP --> inosine --> hypoxanthine, which accounted for >90% of the evoked tritium release. It was surprising that adenosine was not released during ATP-depleting conditions unless AMP deaminase and adenosine deaminase were inhibited. Inosine release was enhanced by inhibition of purine nucleoside phosphorylase; ENT2 transporters mediated the release of adenosine or inosine. However, inhibition of AMP deaminase/adenosine deaminase or purine nucleoside phosphorylase during ATP depletion produced release of adenosine or inosine, respectively, via the rENT2 transporter. This indicates that C6 glioma cells possess primarily rENT2 nucleoside transporters that function in adenosine uptake but that intracellular metabolism prevents the release of adenosine from these cells even during ATP-depleting conditions.
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PMID:Purine uptake and release in rat C6 glioma cells: nucleoside transport and purine metabolism under ATP-depleting conditions. 1098 33

Considering the existing interactions between ethanol and adenosine, the influence of the genetic impairment of the adenosine A(2A) receptor has been examined upon the seizures occurring at the cessation of chronic ethanol intake or 'ethanol withdrawal' in male mice. Acute clearance of ethanol did not differ between adenosine A(2A) receptor knockout and wild-type mice. Mice were exposed for 10 days to a diet consisting of a milky chocolate drink that contained increasing concentrations (1.8, 3.6 and 6.3% v/v) of ethanol. Adenosine A(2A) receptor knockout mice ingested similar amounts of the fluid, either containing alcohol or not, as did the controls. The severity of handling-induced convulsions during withdrawal was significantly reduced in the adenosine A(2A) receptor knockout mice as compared with their wild-type controls. The selective adenosine A(2A) receptor antagonist ZM 241385 (20 mg/kg) also significantly attenuated the intensity of withdrawal-induced seizures occurring in wild-type male mice when intraperitoneally administered twice daily during the last 5 days of the forced alcohol intake. These results suggest that selective adenosine A(2A) receptor antagonists may be useful in the treatment of alcohol withdrawal.
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PMID:Absence of the adenosine A(2A) receptor or its chronic blockade decrease ethanol withdrawal-induced seizures in mice. 1116 35

Animals lacking cellular prion protein (PrP(c)) expression are more susceptible to seizures. Adenosine is an endogenous anticonvulsant agent and it levels in the synaptic cleft are regulated by ectonucleotidases. We evaluated ectonucleotidase activities in synaptosomes from hippocampus and cerebral cortex of adult PrP(c) null mice and wild-type mice (genetic background 129/Sv X C57BL/6J). There was an increase (47%) in adenosine triphosphate (ATP) hydrolysis in hippocampal synaptosomes of PrP(c) knockout mice as compared with the wild-type animals. In cortical synaptosomes, ATP hydrolysis was similar in both PrP(c) mice and controls. However, there was a significant decrease in adenosine diphosphate (ADP) hydrolysis in both hippocampal (-39%) and cortical (-25%) synaptosomes in PrP(c) null animals compared to wild-type mice. Changes in brain ectonucleotidases activities related to modifications in the PrP(c) expression may contribute, at least in part, to the higher sensitivity to seizures of PrP(c) null mice.
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PMID:Changes in cortical and hippocampal ectonucleotidase activities in mice lacking cellular prion protein. 1123 19

Adenosine is a modulator that has a pervasive and generally inhibitory effect on neuronal activity. Tonic activation of adenosine receptors by adenosine that is normally present in the extracellular space in brain tissue leads to inhibitory effects that appear to be mediated by both adenosine A1 and A2A receptors. Relief from this tonic inhibition by receptor antagonists such as caffeine accounts for the excitatory actions of these agents. Characterization of the effects of adenosine receptor agonists and antagonists has led to numerous hypotheses concerning the role of this nucleoside. Previous work has established a role for adenosine in a diverse array of neural phenomena, which include regulation of sleep and the level of arousal, neuroprotection, regulation of seizure susceptibility, locomotor effects, analgesia, mediation of the effects of ethanol, and chronic drug use.
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PMID:The role and regulation of adenosine in the central nervous system. 1128 4

Adenosine is an inhibitor of neuronal activity in the brain. The local release of adenosine from grafted cells was evaluated as an ex vivo gene therapy approach to suppress synchronous discharges and epileptic seizures. Fibroblasts were engineered to release adenosine by inactivating the adenosine-metabolizing enzymes adenosine kinase and adenosine deaminase. After encapsulation into semipermeable polymers, the cells were grafted into the brain ventricles of electrically kindled rats, a model of partial epilepsy. Grafted rats provided a nearly complete protection from behavioral seizures and a near-complete suppression of afterdischarges in electroencephalogram recordings, whereas the full tonic-clonic convulsions in control rats remained unaltered. Thus, the local release of adenosine resulting in adenosine concentrations <25 nM at the site of action is sufficient to suppress seizure activity and, therefore, provides a potential therapeutic principle for the treatment of drug-resistant partial epilepsies.
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PMID:Grafts of adenosine-releasing cells suppress seizures in kindling epilepsy. 1140 69

1. In the present study, the effects of the administration of adenosine on absence seizures were investigated in the Wistar Albino Glaxo/Rijswijk (WAG/Rij) strain of rats, which are an adequate model for human absence epilepsy. 2. After baseline electroencephalogram (EEG) recording, adenosine was injected intraperitoneally (i.p.) at doses of 6, 30 and 120 mg/kg and EEG recordings were continued for 1 h postinjection. In addition, to enable evaluation of the contribution of peripheral factors to the occurrence of spike-wave discharges (SWD) after adenosine injection, arterial blood pressure and rectal temperature were also recorded. 3. Injection of adenosine induced a dose-dependent increase in the appearance of SWD. The number and total duration of SWD were found to be significantly increased after 30 and 120 mg/kg adenosine (P < 0.05). Adenosine also induced a fall in both blood pressure and body temperature in all experimental groups. 4. These results show that peripheral administration of adenosine promotes absence seizures. It is likely that the lowering of blood pressure and body temperature and the activation of sensory afferents after adenosine injection may contribute to the facilitation of SWD observed in the present study.
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PMID:Effects of adenosine administration on spike-wave discharge frequency in genetically epileptic rats. 1147 30

Clinical observations indicate that seizures induced by hypoxia are common kind of convulsive activity in both infants and elderly patients. The occurrence of seizure episode during hypoxia is important risk factor of epilepsy development in the future. Experimental hypoxia was obtained by exposure of adult (20-23 g) Albino Swiss mice to spontaneous breathing in gas mixture composed of 5% oxygen and 95% nitrogen. The latency time to convulsive activity was determined. Single sublethal episode of seizures induced by hypoxia (HS) resulted in higher susceptibility to pentetrazol (PTZ), bicuculline (BCC), N-methyl-D-aspartic acid (NMDA) but not in electrically induced convulsions. Adenosine A1 receptor agonist, R(-)N6-(2-phenyl-isopropyl)adenosine (R-PIA) (0.01; 0.05; 0.1 mg/kg, i.p.) prolonged the latency to HS-induced convulsions. A1 receptor antagonist, 8-cyclopentyltheophylline (CPT), reversed the protective action of R-PIA. A2 receptor agonist, N(6)-[2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)]ethyladenosine (DPMA), only at the highest dose (5 mg/kg i.p.) prolonged the latency time to convulsive activity. This effect was only partially reversed by A2 antagonist 3,7-dimethyl-1-propargylxanthine (DMPX). Administered immediately after episode of HS R-PIA diminished the higher susceptibility to PTZ, BCC, NMDA at 3rd day after HS, while DPMA appeared to be ineffective. These results confirm the important role of adenosine A1 receptor agonist in protection against acute and chronic epileptogenic effect of hypoxia. The role of adenosine A2 receptors seems to be of minor importance.
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PMID:Effect of adenosine A1 and A2 receptor stimulation on hypoxia-induced convulsions in adult mice. 1178 19

Adenosine is an endogenous modulator that has an inhibitory effect on neuronal activity. The aim of this work was to investigate the role of aminophylline, an adenosine receptor antagonist, on the long-term effects of status epilepticus (SE) in the developing brain. Four groups of rats at the postnatal age of 12 days were intraperitoneally administered with saline, aminophylline (50 mg/kg), lithium-pilocarpine (Li-PC) (3 mEq/kg-60 mg/kg), and Li-PC plus aminophylline, respectively. The four groups were tested for spatial memory using the Morris water maze task at P80 and motor performance by the Rotarod test at P100. The brains were then analyzed with cresyl violet stain for histological lesions and evaluated for mossy fiber sprouting with the Timm stain. At the acute stage, all rats subjected to Li-PC developed SE and no seizures were elicited in the saline-treated or aminophylline-treated rats. The seizure duration was longer in the Li-PC plus aminophylline group (346.9+/-32.7 min) as compared with that in the Li-PC group (265.2+/-9.8 min). The difference of mortality was not significant. Rats without seizures exhibited no motor imbalance, spatial deficits, or morphological changes. The rats with Li-PC-induced SE demonstrated spatial memory deficits without motor incoordination or morphological changes. However, the rats subjected to Li-PC plus aminophylline exhibited motor impairment and morphological changes, including neuronal cell loss in CA1 area and increased mossy fiber sprouting in CA3 area. In addition, the rats of Li-PC plus aminophylline had greater spatial memory deficits than that seen in rats with Li-PC. We concluded that an adenosine receptor antagonist, such as aminophylline, had synergistic effects on the SE-induced long-term deficit of cognition and motor performance in the developing brain. The present study may provide experimental evidence and lead to novel therapeutic interventions.
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PMID:Aminophylline exacerbates status epilepticus-induced neuronal damages in immature rats: a morphological, motor and behavioral study. 1207 43

Adenosine has been shown to be a major regulator in convulsive disorders exerting its anticonvulsant effects on various seizure models. The ectonucleotidase pathway is an important metabolic source of extracellular adenosine. In this study, we evaluated ATP, ADP and AMP hydrolysis in rat serum after a single convulsive injection of pentylenetetrazol (PTZ). The animals were sacrificed at 5 and 30 min, 1, 5, 12, 24 and 48 h after an intraperitoneal injection of PTZ (60 mg/kg). ATP, ADP and AMP hydrolysis by rat blood serum were significantly increased (40-50%) until 24 h after PTZ injection. There were no significant differences in the nucleotide hydrolysis when the in vitro effect of different concentrations of PTZ was analyzed. Changes in nucleotide hydrolysis observed after acute administration of PTZ could not be attributed to phosphodiesterase activity since PTZ-treated rats did not demonstrate significant differences in the hydrolysis of the substrate marker of this enzyme when compared with control rats. These results suggest that the stimulation of the nucleotidase pathway may play an important role in attenuating seizure activity.
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PMID:Increase of nucleotidase activities in rat blood serum after a single convulsive injection of pentylenetetrazol. 1210 46


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